Cell-death sex differences

A protein involved in Drosophila courtship produces sexually dimorphic neural circuitry in the fly brain, according to a letter in this week's Nature. This protein establishes a circuit of neurons in males that feeds into brain areas known to be involved in male courting behaviors. Corresponding neurons in females, which lack this protein, die through programmed cell death, the authors say.

"They show very clearly that cell death seems to be involved in at least some aspects of a sexually dimorphic nervous system," said Stephen Goodwin of the University of Glasgow in Scotland, who was not involved in the study.

The gene fruitless (fru) is transcribed in both females and males but then is spliced differently in each sex. Functional Fru protein is translated only in males, first author Ken-ichi Kimura of Hokkaido University of Education in Iwamizawa, Japan, told The Scientist in an Email.

Recent work established that Fru is necessary -- and sufficient -- to induce normal male courtship behaviors in flies. This and other studies found no sexual dimorphism in neuronal anatomy, Kimura said, which has led scientists to speculate that Fru may specify functional, but not structural, differences.

However, Kimura and his colleagues discovered sex differences in the number of cells transcribing fru in the optic lobe and in a region dorsal to the antennal lobe. The somata of the antennal-lobe neurons form a cluster called "neurons medially located, just above antennal lobe" (mAL), and the researchers focused on these neurons for further study.

Male flies have about 30 Fru-expressing neurons in the mAL cluster, while females have only about 5 homologous cells, the authors found. They also found obvious differences in morphology. Male neurons extend bilateral projections, while female neurons send only contralateral projections. Female mAL neurons also show forked arborization, while male neurons never show this pattern.

Kimura and his co-workers next examined the timing of mAL neuronal proliferation during development. They found that proliferation stopped in females by the late larval to early pupal stage but continued in males. When the researchers disabled crucial cell-death genes in female flies, however, mAL neurons continued to proliferate at a male-like rate, which suggests that many more mAL neurons develop in females but then die through programmed cell death, Kimura said.

Kimura's study is "the first report I'm aware of showing that neurons in females undergo cell death since they don't have any Fru protein," said Barbara Taylor of Oregon State University in Corvallis, who was not involved in the study. "It really fits the model we have for how Fru works," Taylor said.

While programmed cell death is likely not the only mechanism that creates differences between female and male brains, "these guys have produced the first data to show at least how some aspects of fruitless specify this dimorphism," Goodwin told The Scientist.

The authors also examined several fru mutant strains, in which males do not produce functional Fru protein. They found that these males had the same number of mAL neurons as normal females and that their neurons had mainly female-like morphology. Conversely, females engineered to express Fru protein in mAL neurons show male-like numbers and shapes of neurons. These mutant females also "vigorously courted partner females," the authors write.

"Fru functions as a male-female switch in the formation of such CNS neural circuits through the regulation of cell death," Kimura said, which gives insight into "how a sexual behavior is constructed in the circuitry of the brain through a function of single gene."

Kimura speculates that signals from female pheromones may feed into male-specific neuronal processes in the mAL. Part of the mAL neural circuit found only in males likely receives input from a brain region known to be involved in gustatory pheromonal detection, he said.